Punctal plug and bioadhesives

ABSTRACT

The present disclosure provides devices and methods for the treatment of ophthalmological conditions such as dry eye. Among the devices provided are punctal plugs and devices for inserting punctal plugs. The punctal plugs may be shaped for insertion in the punctum and/or the canaliculus. They may also be coated with a bioadhesive. Methods for inserting the punctal plugs are provided, as well as methods for preparing bioadhesive-coated punctal plugs. A method is also provided to treat dryeye using a bioadhesive without use of a punctal plug.

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/239,006, filed Oct. 8, 2015, the contents of whichare fully incorporated by reference herein.

BACKGROUND OF THE INVENTION

The invention concerns devices for intubation of the lacrimal duct of aneye for treatment of any of various disorders of the eye, including inparticular “dry eye”, also known as sicca syndrome.

As shown in FIG. 1, the lacrimal gland secretes tears which drain intothe inferior nasal meatus via the lacrimal duct after moistening theocular surface having the cornea and conjunctiva. The lacrimal ductconsists of the upper punctum, lower punctum, vertical portion of theupper punctum, vertical portion of the lower punctum, boundary portionbetween the upper vertical and horizontal portions, boundary portionbetween the lower vertical and horizontal portions, upper horizontalportion, lower horizontal portion, common canaliculus, lacrimal sac, andnasolacrimal duct. The lower end of the nasolacrimal duct opens into theinferior nasal meatus.

Patients with dry eye have a deficiency of tears, which are veryimportant for function and comfort of the eye. Dry eye symptoms includeasthenopia, waking irritation, grittiness, foreign body sensation,scratchiness, soreness, difficulty to open the eyes in an airconditioned room, injection, burning, etc. In dry eye, tears drain awayfrom the eye, more quickly than they should, via the lacrimal duct.

To suppress tear drainage, the upper punctum can be occluded using apunctal plug (sometimes referred to as a punctum plug, lacrimal punctumplug, or lacrimal insert) inserted into the upper punctum, and/or thelower punctum can be occluded using a punctal plug inserted into thelower punctum.

By blocking the upper punctum and lower punctum like this, tears areaccumulated in the conjunctival sac, and in many cases dry eye symptomsimprove.

Punctal plugs in current use are either “temporary” or “permanent”.So-called temporary punctal plugs typically are simple tubularstructures made of collagen or synthetic collagen, and they are designedto last for about ten days to about three months, over which time theydissolve or fall out. So-called permanent punctal plugs typically aremore complex, contoured devices usually made of silicone, and, whilethey do not dissolve, they can cause irritation and frequently fall out.Examples of punctal plugs are described in U.S. Pat. No. 3,949,750 toFreeman; U.S. Pat. No. 5,283,063 to Freeman; U.S. Pat. No. 5,417,651 toGuena et al.; U.S. Pat. No. 6,027,470 to Mendius; U.S. Pat. No.6,238,363 to Kurihashi; U.S. Pat. No. 6,290,684 to Herrick; U.S. Pat.No. 7,785,285 to Kurihashi; U.S. Pat. No. 8,439,865 to Lust et al.; U.S.Pat. No. 8,628,792 to Utkhede et al.; U.S. Pat. No. 8,795,711 to deJuan, Jr. et al.; and U.S. Pat. No. 8,821,457 to Beeley et al., theentire contents of all of which are incorporated herein by reference.

SUMMARY OF THE INVENTION

An aspect of the invention is a punctal plug comprising a bodycomprising a biodegradable polymer, wherein said biodegradable polymeris not collagen or synthetic collagen.

An aspect of the invention is a punctal plug comprising a bodycomprising a biocompatible elastic polymer, wherein said biocompatibleelastic polymer is not silicone.

An aspect of the invention is an insertion device suitable for use ininserting or removing a punctal plug of the invention.

An aspect of the invention is a method of using a punctal plug,comprising the steps of applying a bioadhesive to a tissue-contactingouter surface of a punctal plug, thereby forming a bioadhesive-coatedpunctal plug; and inserting the bioadhesive-coated punctal plug into apunctum of an eye.

An aspect of the invention is a method of treating dry eye, comprisinginstalling into a punctum opening of an eye of a subject in need thereofa punctal plug of the invention.

An aspect of the invention is a punctal plug, comprising a bioadhesivedisposed on a surface oriented to contact tissue of a subject.

An aspect of the invention is a kit comprising a punctal plug and abioadhesive. In certain embodiments, the punctal plug may be a punctalplug as described above.

An aspect of the invention is a method of treating an ophthalmologicalcondition such as dry-eye, comprising inserting a bioadhesive into thepunctum or the canaliculus.

An aspect of the invention is a kit comprising a bioadhesive and anapplicator suitable for inserting the bioadhesive into the punctum orthe canaliculus, or both.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 depicts eye tear system anatomy. Indicated are (a), tear/lacrimalgland; (b), superior lacrimal punctum; (c), superior lacrimal canal;(d), tear/lacrimal sac; (e), inferior lacrimal punctum; (f), inferiorlacrimal canal; (g), nasolacrimal canal.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a longer lasting version of a temporary punctalplug. Currently, temporary punctal plugs are made out of collagen orsynthetic collagen. In accordance with the invention, a temporary plugwith a longer useful life is constructed using a longer lastingbiodegradable polymer.

So-called “permanent” punctal plugs are currently made out of silicone.In accordance with the invention, a permanent plug is made using anothermaterial such as a biocompatible polymer, preferably a biocompatibleelastic polymer.

The invention further provides a punctal plug with a thin, contouredexposed edge possibly using silicone or another biocompatible polymerwith malleable property that can mold to punctal anatomy. This punctalplug may or may not have bioadhesive attached.

A feature of certain embodiments of the invention is the use of abioadhesive to keep the plug in place. This adhesive may be synthetic ornatural.

In certain embodiments, the punctal plug has textured surface to promoteits staying in place, e.g. a “shark skin” surface or a gecko setae-likesurface.

The invention further provides a punctal plug with intracanalicularextension. The plug portion has any of the possible attributes justdescribed. The intracanalicular extension can be a liquid-like,gelatinous, or semi-solid material that becomes more formed and mold tothe canaliculus. It may or may not have a bioadhesive on its surface orwithin its structure. Existing expandable “smart plugs”, which arestrictly intracanalicular, have been plagued with problems because theymigrate into the lacrimal sac and cause infections. In contrast, in thisembodiment of the invention, the punctal plug portion keeps theintracanalicular portion from migrating into the lacrimal sac, and thecanalicular portion helps prevent the plug from extruding from thepunctum.

An aspect of the invention is a punctal plug comprising a bodycomprising a biodegradable polymer, wherein said biodegradable polymeris not collagen or synthetic collagen.

In certain embodiments, the biodegradable polymer is selected frompoly(alpha-esters); polyglycolide; polylactide;polylactide-co-glycolide; polyhydroxyalkanoates; polycaprolactone;polypropylene fumarate; polyanhydrides; polyacetals; polyortho esters;polycarbonates; polyurethanes; polyphosphazenes; polyphosphoesters;polyester-ester; polyamide-ester; polyanhydride-ester; enzymaticallydegradable polymers; synthetic polyethers; polyethylene glycol (PEG);polypropylene glycol (PPG); PEGdiacrylate (PEGDA); PEGdimethacrylate(PEGDMA); PEGDA and PEGDMA with other acrylates and methacrylate;degradable polymer proteins and poly(amino acids) selected from elastin,elastin-like polypeptides, albumin, natural poly(amino acids),poly(γ-glutamic acid), poly L-lysine, poly L-glutamic acid, polyaspartic acid, polysaccharides, hyaluronic acid methacrylate, hyaluronicacid chondroitin sulfate, and chitosan alginate; and any combinationthereof. In certain embodiments, the biodegradable polymer excludes anyone or more of poly(alpha-esters); polyglycolide; polylactide;polylactide-co-glycolide; polyhydroxyalkanoates; polycaprolactone;polypropylene fumarate; polyanhydrides; polyacetals; polyortho esters;polycarbonates; polyurethanes; polyphosphazenes; polyphosphoesters;polyester-ester; polyamide-ester; polyanhydride-ester; enzymaticallydegradable polymers; synthetic polyethers; polyethylene glycol (PEG);polypropylene glycol (PPG); PEGdiacrylate (PEGDA); PEGdimethacrylate(PEGDMA); PEGDA and PEGDMA with other acrylates and methacrylate;degradable polymer proteins and poly(amino acids) selected from elastin,elastin-like polypeptides, albumin, natural poly(amino acids),poly(γ-glutamic acid), poly L-lysine, poly L-glutamic acid, polyaspartic acid, polysaccharides, hyaluronic acid methacrylate, hyaluronicacid chondroitin sulfate, and chitosan alginate.

An aspect of the invention is a punctal plug comprising a bodycomprising a biocompatible elastic polymer, wherein said biocompatibleelastic polymer is not silicone.

In certain embodiments, the biocompatible elastic polymer is selectedfrom Acrysof (copolymer of phenylethyl acrylate and phenylethylmethacrylate cross linked with butanediol diacrylate); natural andsynthetic forms of amniotic membrane; degradable polymer proteins andpoly(amino acids) selected from elastin, elastin-like polypeptides,albumin, natural poly(amino acids), poly(γ-glutamic acid), polyL-lysine, poly L-glutamic acid, poly aspartic acid, polysaccharides,hyaluronic acid methacrylate, hyaluronic acid chondroitin sulfate, andchitosan alginate; Dow Corning elastomers; enzymatically degradablepolymers; ester-based thermoplastic polyurethane elastomer (TPUR)compounds; ether-based thermoplastic polyurethane elastomer (TPUR)compounds; Hoya (cross linked copolymer of phenylethyl methacrylate andn-butyl acrylate, fluoroalkyl methacrylate); hydrogels; hydrophilicacrylics; hydrophobic acrylics (foldable and non-foldable);hydroxyethylmethacrylate (HEMA) hydrophilic polymer; methylmethacrylate; nylon; PEGDA and PEGDMA with other acrylates andmethacrylate; PEGdiacrylate (PEGDA); PEGdimethacrylate (PEGDMA);poliglecaprone suture; poly(alpha-esters); polyacetals;polyamide-esters; polyamides; polyanhydride-esters; polyanhydrides;polycaprolactones; polycarbonates; polydioxanones; polyester urethanes;polyesters; polyether polyester copolymers; polyether urethanes;polyether-ester block copolymer thermoplastic elastomer (TEEE)compounds; polyethylene glycol (PEG); polyethylenes; polyglactin 910suture; polyglycolic acid suture; polyglycolides; polyhydroxyalkanoates;polylactides; polylactide-co-glycolides; polymethylmethacrylate (PMMA);polyortho esters; polyphosphazenes; polyphosphoesters; polypropylenes;polypropylene fumarate; polypropylene glycol (PPG); polypropylene oxide;polytetrafluorethylene (Teflon); polyurethanes; RTP Co. thermoplasticelastomers; saturated styrenic block copolymer thermoplastic elastomers;SILASTIC® (medical adhesive silicone, Dow Corning); silicone hydrogels;silk; synthetic polyethers; Tecnis acrylic (copolymer of ethyl acrylateethyl methacrylate, 2,2,2-trifluorethyl methacrylate, cross linked withethylene glycol dimethacrylate); thermoplastic polyolefin elastomer(TEO) compounds; and thermoplastic vulcanizate (TPV) compounds.

In certain embodiments, the biocompatible elastic polymer excludes anyone or more of Acrysof (copolymer of phenylethyl acrylate andphenylethyl methacrylate cross linked with butanediol diacrylate);natural and synthetic forms of amniotic membrane; degradable polymerproteins and poly(amino acids) selected from elastin, elastin-likepolypeptides, albumin, natural poly(amino acids), poly(γ-glutamic acid),poly L-lysine, poly L-glutamic acid, poly aspartic acid,polysaccharides, hyaluronic acid methacrylate, hyaluronic acidchondroitin sulfate, and chitosan alginate; Dow Corning elastomers;enzymatically degradable polymers; ester-based thermoplasticpolyurethane elastomer (TPUR) compounds; ether-based thermoplasticpolyurethane elastomer (TPUR) compounds; Hoya (cross linked copolymer ofphenylethyl methacrylate and n-butyl acrylate, fluoroalkylmethacrylate); hydrogels; hydrophilic acrylics; hydrophobic acrylics(foldable and non-foldable); hydroxyethylmethacrylate (HEMA) hydrophilicpolymer; methyl methacrylate; nylon; PEGDA and PEGDMA with otheracrylates and methacrylate; PEGdiacrylate (PEGDA); PEGdimethacrylate(PEGDMA); poliglecaprone suture; poly(alpha-esters); polyacetals;polyamide-esters; polyamides; polyanhydride-esters; polyanhydrides;polycaprolactones; polycarbonates; polydioxanones; polyester urethanes;polyesters; polyether polyester copolymers; polyether urethanes;polyether-ester block copolymer thermoplastic elastomer (TEEE)compounds; polyethylene glycol (PEG); polyethylenes; polyglactin 910suture; polyglycolic acid suture; polyglycolides; polyhydroxyalkanoates;polylactides; polylactide-co-glycolides; polymethylmethacrylate (PMMA);polyortho esters; polyphosphazenes; polyphosphoesters; polypropylenes;polypropylene fumarate; polypropylene glycol (PPG); polypropylene oxide;polytetrafluorethylene (Teflon); polyurethanes; RTP Co. thermoplasticelastomers; saturated styrenic block copolymer thermoplastic elastomers;SILASTIC® (medical adhesive silicone, Dow Corning); silicone hydrogels;silk; synthetic polyethers; Tecnis acrylic (copolymer of ethyl acrylateethyl methacrylate, 2,2,2-trifluorethyl methacrylate, cross linked withethylene glycol dimethacrylate); thermoplastic polyolefin elastomer(TEO) compounds; and thermoplastic vulcanizate (TPV) compounds.

In accordance with any of the foregoing aspects and embodiments, incertain embodiments the body comprises a flared proximal end.

In accordance with any of the foregoing aspects and embodiments, incertain embodiments the body comprises a flared midsection.

In accordance with any of the foregoing aspects and embodiments, incertain embodiments the body comprises a flared distal end.

In accordance with any of the foregoing aspects and embodiments, incertain embodiments the body comprises a valve or septum through which amaterial can be injected or introduced into the punctal plug.

In accordance with any of the foregoing aspects and embodiments, incertain embodiments the punctal plug further comprises a bioadhesivedisposed on a surface oriented to contact tissue of a subject.

An aspect of the invention is a punctal plug, comprising a bioadhesivedisposed on a surface oriented to contact tissue of a subject. Thepunctal plug may be a punctal plug as described above, or may be anyother punctal plug known to those of skill in the art. In certainembodiments, the punctal plug comprises a body and a bioadhesive,wherein the bioadhesive is disposed on a tissue-contacting outer surfaceof the body. In certain embodiments, the punctal plug comprises a bodycomprising a biodegradable polymer, wherein said biodegradable polymeris collagen or synthetic collagen. In certain embodiments, the punctalplug comprises a body comprising a biodegradable polymer, wherein saidbiodegradable polymer is not collagen or synthetic collagen. In certainembodiments, the punctal plug comprises a body comprising abiocompatible elastic polymer, wherein said biocompatible elasticpolymer is silicone. In certain embodiments, the punctal plug comprisesa body comprising a biocompatible elastic polymer, wherein saidbiocompatible elastic polymer is not silicone.

In certain embodiments, the bioadhesive is selected from thebioadhesives described herein, such as spider web-based bioadhesive,gecko lizard-based bioadhesive, fibrin glue, gelatin-based glue,gelatin-resorcinol-formaldehyde/glutaraldehyde (GRF or GRFG),glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanocrylate, n-butyl-2-cyanoacrylate (INDERMIL®), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabledmussel-inspired bioadhesives (iCMBA), and any combination thereof. Incertain embodiments, the bioadhesive can exclude any one or morebioadhesives selected from spider web-based bioadhesive, geckolizard-based bioadhesive, fibrin glue, gelatin-based glue,gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG),glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanocrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), and citrate-enabledmussel-inspired bioadhesives (iCMBA).

In certain embodiments, the bioadhesive is a mussel adhesive protein(MAP), synthetic MAP, or a MAP-inspired polymer such as are described inU.S. Pat. No. 8,673,286 to Messersmith et al., and WO 2013/123946 toAarhus Universitet, the entire contents of which are incorporated hereinby reference. As disclosed in Messersmith et al., MAPs are remarkableunderwater adhesive materials secreted by certain marine organisms whichform tenacious bonds to the substrates upon which they reside. Duringthe process of attachment to a substrate, MAPs are secreted as adhesivefluid precursors that undergo a crosslinking or hardening reaction whichleads to the formation of a solid adhesive plaque. One of the uniquefeatures of MAPs is the presence of L-3-4-dihydroxyphenylalanine (DOPA),an unusual amino acid which is believed to be responsible for adhesionto substrates through several mechanisms that are not yet fullyunderstood. The observation that mussels adhere to a variety of surfacesin nature (metal, metal oxide, polymer) led to a hypothesis thatDOPA-containing peptides can be employed as the key components ofsynthetic medical adhesives. Messersmith et al. specifically disclosesDOPA (and related multihydroxyphenyl derivatives)-functionalizedpolyalkylene oxide materials that are useful as adhesives.

In certain embodiments, the bioadhesive is biodegradable. For example,the bioadhesive may be selected from natural and synthetic forms ofamniotic membrane, fibrin glue, MAP, synthetic MAP, or synthetic MAPcoated by DOPA-functionalized PEG and PCL. In other embodiments, thebioadhesive may be an isocyanatoethylmethacrylate-based bioadhesive (asdescribed in Ferreira et al., Int J. Pharm, 2008 Mar. 20;352(1-2):172-81); a biodegradable urethane-based bioadhesive (asdescribed in J Mater Sci Mater Med. 2008 January; 19(1):111-20); or apoly-dihydroacetate-based bioadhesive (as described in Singh et al., J.Am. Col. Surgeons, September 2008 Volume 207, Issue 3, Supplement, PageS64).

In certain embodiments, the bioadhesive comprises a textured surface,e.g. a “shark skin” surface or a gecko setae-like surface. In certainembodiments, the bioadhesive imparts a textured surface, e.g. a “sharkskin” surface or a gecko setae-like surface.

In certain embodiments, the bioadhesive is applied to the punctal plugat the time of installation of the plug into a subject.

In accordance with any of the foregoing aspects and embodiments, thepunctal plug further comprises a core or reservoir at least partiallywithin the body of the punctal plug, wherein the core or reservoircomprises a therapeutic agent.

An aspect of the invention is an insertion device suitable for use ininserting or removing a punctal plug of the invention. In certainembodiments, the punctal plug comprises an opening or blind holeconstructed and arranged so as to accept an insertion device. Theinsertion device is constructed and arranged so as to releasably engagethe punctal plug for purposes of inserting the punctal plug into apunctum opening of an eye. The insertion device can be constructed andarranged so as to releasably engage the punctal plug for purposes ofremoving the punctal plug from a punctum opening of an eye.

An aspect of the invention is a kit comprising a punctal plug and abioadhesive. In certain embodiments, the punctal plug may be a punctalplug as described above.

In certain embodiments, the bioadhesive is selected from thebioadhesives described herein, such as spider web-based bioadhesive,natural and synthetic forms of amniotic membrane, fibrin glue,gelatin-based glue, gelatin-resorcinol-formaldehyde/glutaraldehyde (GRFor GRFG), glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabledmussel-inspired bioadhesives (iCMBA), MAP-inspired polymers, and anycombination thereof. In certain embodiments, the bioadhesive can excludeany one or more bioadhesives selected from spider web-based bioadhesive,gecko lizard-based bioadhesive, natural and synthetic forms of amnioticmembrane, fibrin glue, gelatin-based glue,gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG),glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanocrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabledmussel-inspired bioadhesives (iCMBA), and MAP-inspired polymers.

In certain embodiments, the bioadhesive is biodegradable. For example,the bioadhesive may be selected from natural and synthetic forms ofamniotic membrane, fibrin glue, MAP, synthetic MAP, or synthetic MAPcoated by DOPA-functionalized PEG and PCL. In other embodiments, thebioadhesive may be an isocyanatoethylmethacrylate-based bioadhesive (asdescribed in Ferreira et al., Int J. Pharm, 2008 Mar. 20;352(1-2):172-81); a biodegradable urethane-based bioadhesive (asdescribed in J Mater Sci Mater Med. 2008 January; 19(1):111-20); or apoly-dihydroacetate-based bioadhesive (as described in Singh et al., J.Am. Col. Surgeons, September 2008 Volume 207, Issue 3, Supplement, PageS64).

The punctal plug may be any suitable punctal plug known to those ofskill in the art. Preferably, the punctal plug is a punctal plug of theinvention.

An aspect of the invention is a method of using a punctal plug,comprising the steps of applying a bioadhesive to a tissue-contactingouter surface of a punctal plug, thereby forming a bioadhesive-coatedpunctal plug; and inserting the bioadhesive-coated punctal plug into apunctum of an eye.

In certain embodiments, the bioadhesive is selected from thebioadhesives described herein, such as spider web-based bioadhesive,gecko lizard-based bioadhesive, natural and synthetic forms of amnioticmembrane, fibrin glue, gelatin-based glue,gelatin-resorcinol-formaldehyde/glutaraldehyde (GRF or GRFG),glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabledmussel-inspired bioadhesives (iCMBA), MAP-inspired polymers, and anycombination thereof. In certain embodiments, the bioadhesive can excludeany one or more bioadhesives selected from spider web-based bioadhesive,gecko lizard-based bioadhesive, natural and synthetic forms of amnioticmembrane, fibrin glue, gelatin-based glue,gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG),glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanocrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabledmussel-inspired bioadhesives (iCMBA), and MAP-inspired polymers.

In certain embodiments, the bioadhesive is biodegradable. For example,the bioadhesive may be selected from natural and synthetic forms ofamniotic membrane, fibrin glue, MAP, synthetic MAP, synthetic MAP coatedby DOPA-functionalized PEG and PCL, or MAP-inspired polymers. In otherembodiments, the bioadhesive may be an isocyanatoethylmethacrylate-basedbioadhesive (as described in Ferreira et al., Int J. Pharm, 2008 Mar.20; 352(1-2):172-81); a biodegradable urethane-based bioadhesive (asdescribed in J Mater Sci Mater Med. 2008 January; 19(1):111-20); or apoly-dihydroacetate-based bioadhesive (as described in Singh et al., J.Am. Col. Surgeons, September 2008 Volume 207, Issue 3, Supplement, PageS64).

In certain embodiments, the punctal plug is a punctal plug of theinvention.

In certain embodiments, the punctal plug is a prior art punctal plug.

An aspect of the invention is a method of treating an ophthalmologicalcondition such as dry-eye, comprising inserting a bioadhesive into thepunctum or the canaliculus. As a result, fluid flow through the punctumor the canaliculus is blocked. This technique allows treatment of dryeye without using a physical punctal plug. The punctum or canaliculus,or both, can be directly glued shut. This avoids the need to manufactureand sterilize the plug itself, and avoids the risk of the plug fallingout.

The bioadhesive may be inserted into the punctum or canaliculus by anysuitable method. In some embodiments, the bioadhesive is applied to anapplicator, and the applicator is then used to insert the bioadhesiveinto the punctum or canaliculus. In some embodiments, the bioadhesive iscontained within a syringe or squeeze ampule, which is used to insertthe bioadhesive into the punctum or canaliculus. If the bioadhesive iscontained within a syringe or other similar device, it may be prefilledor filled just prior to insertion.

In some embodiments, the bioadhesive may be selected from thebioadhesives described herein, such as spider web-based bioadhesive,gecko lizard-based bioadhesive, natural and synthetic forms of amnioticmembrane, fibrin glue, gelatin-based glue,gelatin-resorcinol-formaldehyde/glutaraldehyde (GRF or GRFG),glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabledmussel-inspired bioadhesives (iCMBA), MAP-inspired polymers, and anycombination thereof. In certain embodiments, the bioadhesive can excludeany one or more bioadhesives selected from spider web-based bioadhesive,gecko lizard-based bioadhesive, natural and synthetic forms of amnioticmembrane, fibrin glue, gelatin-based glue,gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG),glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate,2-octylcyanocrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethyleneglycol (PEG)-based hydrogel sealant, urethane-based adhesive, musseladhesive protein (MAP), synthetic MAP, synthetic MAP coated byDOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabledmussel-inspired bioadhesives (iCMBA), and MAP-inspired polymers.

In certain embodiments, the bioadhesive is biodegradable. For example,the bioadhesive may be selected from natural and synthetic forms ofamniotic membrane, fibrin glue, MAP, synthetic MAP, synthetic MAP coatedby DOPA-functionalized PEG and PCL, or MAP-inspired polymers. In otherembodiments, the bioadhesive may be an isocyanatoethylmethacrylate-basedbioadhesive (as described in Ferreira et al., Int J. Pharm, 2008 Mar.20; 352(1-2):172-81; a biodegradable urethane-based bioadhesive (asdescribed in J Mater Sci Mater Med. 2008 January; 19(1):111-20); or apoly-dihydroacetate-based bioadhesive (as described in Singh et al., J.Am. Col. Surgeons, September 2008 Volume 207, Issue 3, Supplement, PageS64).

An aspect of the invention is a kit comprising a bioadhesive and anapplicator suitable for inserting the bioadhesive into the punctum orthe canaliculus, or both. In certain embodiments, the bioadhesive is abioadhesive as described above. In certain embodiments, the bioadhesiveis biodegradable, and may be selected from the biodegradablebioadhesives described above. In certain embodiments, the kit comprisestwo applicators: one suitable for inserting the bioadhesive into thepunctum and one suitable for inserting the bioadhesive into thecanaliculus.

EXAMPLES

Having now described the present invention in detail, the same will bemore clearly understood by reference to the following examples, whichare included herewith for purposes of illustration only and are notintended to be limiting of the invention.

Example 1

A punctal plug is manufactured out of a biomaterial substantially asdescribed herein. In one embodiment, the punctal plug is a “temporary”punctal plug. In one embodiment, the punctal plug is a “permanent”punctal plug.

Example 2

A punctal plug of Example 1 is coated with a bioadhesive substantiallyas described herein prior to insertion of the punctal plug into apunctum opening of an eye. The bioadhesive coating is applied by any oneor more of painting, dipping or submerging, rolling, or the like, withor in the bioadhesive. The punctal plug is optionally held in place bythe operator long enough for the bioadhesive to cure or adhere to tissuesufficiently to stabilize the plug in place. Preferably the timerequired for such curing or adhering is about 15 seconds to about 5minutes.

Example 3

A prior art punctal plug is coated with a bioadhesive substantially asdescribed herein prior to insertion of the punctal plug into a punctumopening of an eye. The bioadhesive coating is applied by any one or moreof painting, dipping or submerging, rolling, or the like, with or in thebioadhesive. The punctal plug is optionally held in place by theoperator long enough for the bioadhesive to cure or adhere to tissuesufficiently to stabilize the plug in place. Preferably the timerequired for such curing or adhering is about 15 seconds to about 5minutes.

Example 4

A syringe is pre-filled with a bioadhesive substantially as describedherein. The syringe is used to insert the bioadhesive into the punctumand canaliculus of a patient's eye, thereby sealing the punctum and thecanaliculus. Preferably the bioadhesive cures, such that fluidtransmission through the punctum and canaliculus is blocked, withinabout 15 seconds to about 5 minutes.

INCORPORATION BY REFERENCE

All patents and published patent applications mentioned in thedescription above are incorporated by reference herein in theirentirety.

EQUIVALENTS

Having now fully described the present invention in some detail by wayof illustration and example for purposes of clarity of understanding, itwill be obvious to one of ordinary skill in the art that the same can beperformed by modifying or changing the invention within a wide andequivalent range of conditions, formulations and other parameterswithout affecting the scope of the invention or any specific embodimentthereof, and that such modifications or changes are intended to beencompassed within the scope of the appended claims.

1. A punctal plug comprising a body comprising a biodegradable polymer, wherein said biodegradable polymer is not collagen or synthetic collagen.
 2. The punctal plug of claim 1, wherein the biodegradable polymer is selected from poly(alpha-esters); polyglycolide; polylactide; polylactide-co-glycolide; polyhydroxyalkanoates; polycaprolactone; polypropylene fumarate; polyanhydrides; polyacetals; polyortho esters; polycarbonates; polyurethanes; polyphosphazenes; polyphosphoesters; polyester-ester; polyamide-ester; polyanhydride-ester; enzymatically degradable polymers; synthetic polyethers; polyethylene glycol (PEG); polypropylene glycol (PPG); PEGdiacrylate (PEGDA); PEGdimethacrylate (PEGDMA); PEGDA and PEGDMA with other acrylates and methacrylate; degradable polymer proteins and poly(amino acids) selected from elastin, elastin-like polypeptides, albumin, natural poly(amino acids), poly(γ-glutamic acid), poly L-lysine, poly L-glutamic acid, poly aspartic acid, polysaccharides, hyaluronic acid methacrylate, hyaluronic acid chondroitin sulfate, and chitosan alginate; and any combination thereof.
 3. A punctal plug comprising a body comprising a biocompatible elastic polymer, wherein said biocompatible elastic polymer is not silicone.
 4. The punctal plug of claim 1, wherein the biocompatible elastic polymer is selected from Acrysof (copolymer of phenylethyl acrylate and phenylethyl methacrylate cross linked with butanediol diacrylate); natural and synthetic forms of amniotic membrane; degradable polymer proteins and poly(amino acids) selected from elastin, elastin-like polypeptides, albumin, natural poly(amino acids), poly(γ-glutamic acid), poly L-lysine, poly L-glutamic acid, poly aspartic acid, polysaccharides, hyaluronic acid methacrylate, hyaluronic acid chondroitin sulfate, and chitosan alginate; Dow Corning elastomers; enzymatically degradable polymers; ester-based thermoplastic polyurethane elastomer (TPUR) compounds; ether-based thermoplastic polyurethane elastomer (TPUR) compounds; Hoya (cross linked copolymer of phenylethyl methacrylate and n-butyl acrylate, fluoroalkyl methacrylate); hydrogels; hydrophilic acrylics; hydrophobic acrylics (foldable and non-foldable); hydroxyethylmethacrylate (HEMA) hydrophilic polymer; methyl methacrylate; nylon; PEGDA and PEGDMA with other acrylates and methacrylate; PEGdiacrylate (PEGDA); PEGdimethacrylate (PEGDMA); poliglecaprone suture; poly(alpha-esters); polyacetals; polyamide-esters; polyamides; polyanhydride-esters; polyanhydrides; polycaprolactones; polycarbonates; polydioxanones; polyester urethanes; polyesters; polyether polyester copolymers; polyether urethanes; polyether-ester block copolymer thermoplastic elastomer (TEEE) compounds; polyethylene glycol (PEG); polyethylenes; polyglactin 910 suture; polyglycolic acid suture; polyglycolides; polyhydroxyalkanoates; polylactides; polylactide-co-glycolides; polymethylmethacrylate (PMMA); polyortho esters; polyphosphazenes; polyphosphoesters; polypropylenes; polypropylene fumarate; polypropylene glycol (PPG); polypropylene oxide; polytetrafluorethylene (Teflon); polyurethanes; RTP Co. thermoplastic elastomers; saturated styrenic block copolymer thermoplastic elastomers; SILASTIC® (medical adhesive silicone, Dow Corning); silicone hydrogels; silk; synthetic polyethers; Tecnis acrylic (copolymer of ethyl acrylate ethyl methacrylate, 2,2,2-trifluorethyl methacrylate, cross linked with ethylene glycol dimethacrylate); thermoplastic polyolefin elastomer (TEO) compounds; and thermoplastic vulcanizate (TPV) compounds.
 5. The punctal plug of any one of claims 1-4, wherein the body comprises a flared proximal end.
 6. The punctal plug of any one of claims 1-5, wherein the body comprises a flared midsection.
 7. The punctal plug of any one of claims 1-6, wherein the body comprises a flared distal end.
 8. The punctal plug of any one of claims 1-7, wherein the punctal plug further comprises a bioadhesive disposed on a surface oriented to contact tissue of a subject.
 9. The punctal plug of claim 8, wherein the bioadhesive is selected from spider web-based bioadhesive, gecko lizard-based bioadhesive, natural and synthetic forms of amniotic membrane, fibrin glue, gelatin-based glue, gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG), glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate, 2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethylene glycol (PEG)-based hydrogel sealant, urethane-based adhesive, mussel adhesive protein (MAP), synthetic MAP, synthetic MAP coated by DOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabled mussel-inspired bioadhesives (iCMBA), and any combination thereof.
 10. The punctal plug of any one of claims 8-9, wherein the bioadhesive is biodegradable.
 11. The punctal plug of any one of claims 8-10, wherein the bioadhesive is applied to the punctal plug at the time of installation of the plug into a subject.
 12. The punctal plug of any one of claims 1-11, further comprising a core or reservoir at least partially within the body of the punctal plug, wherein the core or reservoir comprises a therapeutic agent.
 13. An insertion device suitable for use in inserting or removing the punctal plug of any one of claims 1-12.
 14. A punctal plug comprising a body and a bioadhesive, wherein the bioadhesive is disposed on a tissue-contacting outer surface of the body.
 15. The punctal plug of claim 14, wherein the bioadhesive is selected from spider web-based bioadhesive, gecko lizard-based bioadhesive, natural and synthetic forms of amniotic membrane, fibrin glue, gelatin-based glue, gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG), glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate, 2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethylene glycol (PEG)-based hydrogel sealant, urethane-based adhesive, mussel adhesive protein (MAP), synthetic MAP, synthetic MAP coated by DOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabled mussel-inspired bioadhesives (iCMBA), and any combination thereof.
 16. The punctal plug of any one of claims 14-15, wherein the bioadhesive is biodegradable.
 17. The punctal plug of any one of claims 14-16, wherein the bioadhesive is applied to the punctal plug at the time of installation of the plug into a subject.
 18. The punctal plug of any one of claims 14-18, further comprising a core or reservoir at least partially within the body of the punctal plug, wherein the core or reservoir comprises a therapeutic agent.
 19. A kit comprising a punctal plug and a bioadhesive.
 20. The kit of claim 19, wherein the bioadhesive is selected from spider web-based bioadhesive, gecko lizard-based bioadhesive, natural and synthetic forms of amniotic membrane, fibrin glue, gelatin-based glue, gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG), glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate, 2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethylene glycol (PEG)-based hydrogel sealant, urethane-based adhesive, mussel adhesive protein (MAP), synthetic MAP, synthetic MAP coated by DOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabled mussel-inspired bioadhesives (iCMBA), and any combination thereof.
 21. The kit of any one of claims 19-20, wherein the bioadhesive is biodegradable.
 22. The kit of any one of claims 19-21, wherein the punctal plug is the punctal plug of any one of claim 1-12 or 14-18.
 23. A method of using a punctal plug, comprising applying a bioadhesive to a tissue-contacting outer surface of a punctal plug, thereby forming a bioadhesive-coated punctal plug; and inserting the bioadhesive-coated punctal plug into a punctum of an eye.
 24. The method of claim 23, wherein the bioadhesive is selected from spider web-based bioadhesive, gecko lizard-based bioadhesive, natural and synthetic forms of amniotic membrane, fibrin glue, gelatin-based glue, gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG), glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate, 2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethylene glycol (PEG)-based hydrogel sealant, urethane-based adhesive, mussel adhesive protein (MAP), synthetic MAP, synthetic MAP coated by DOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabled mussel-inspired bioadhesives (iCMBA), and any combination thereof.
 25. The method of any one of claims 23-24, wherein the bioadhesive is biodegradable.
 26. The method of any one of claims 23-25, wherein the punctal plug is the punctal plug of any one of claim 1-12 or 14-18.
 27. A method of treating dry-eye comprising inserting a bioadhesive into the punctum or the canaliculus.
 28. The method of claim 27, wherein the bioadhesive is selected from spider web-based bioadhesive, gecko lizard-based bioadhesive, natural and synthetic forms of amniotic membrane, fibrin glue, gelatin-based glue, gelatin-resorcin-formaldehyde/glutaraldehyde (GRF or GRFG), glutaraldehyde glyoxal, albumin-glutaraldehyde, cyanoacrylate, 2-octylcyanoacrylate, n-butyl-2-cyanoacrylate (INDERMIL), polyethylene glycol (PEG)-based hydrogel sealant, urethane-based adhesive, mussel adhesive protein (MAP), synthetic MAP, synthetic MAP coated by DOPA-functionalized PEG and polycaprolactone (PCL), citrate-enabled mussel-inspired bioadhesives (iCMBA), and any combination thereof.
 29. The method of any one of claim 27 or 28, comprising inserting the bioadhesive into the punctum and the canaliculus.
 30. The method of any one of claim 27 or 28, comprising inserting the bioadhesive into the punctum alone.
 31. The method of any one of claim 27 or 28, comprising inserting the bioadhesive into the canaliculus alone.
 32. The method of any one of claims 27-31, wherein the bioadhesive is biodegradable.
 33. The method of any one of claims 27-32, wherein inserting the bioadhesive into the punctum or the canaliculus comprises using a syringe, ampoule, or applicator to insert the bioadhesive into the punctum or the canaliculus. 